Selective Suppression of Interleukin-12 Induction after Macrophage Receptor Ligation

Abstract

Interleukin (IL)-12 is a monocyte- and macrophage-derived cytokine that plays a crucial role in both the innate and the acquired immune response. In this study, we examined the effects that ligating specific macrophage receptors had on the induction of IL-12 by lipopolysaccharide (LPS). We report that ligation of the macrophage Fcγ, complement, or scavenger receptors inhibited the induction of IL-12 by LPS. Both mRNA synthesis and protein secretion were diminished to near-undetectable levels following receptor ligation. Suppression was specific to IL-12 since IL-10 and tumor necrosis factor-α (TNF-α) production were not inhibited by ligating macrophage receptors. The results of several different experimental approaches suggest that IL-12 downregulation was due to extracellular calcium influxes that resulted from receptor ligation. First, preventing extracellular calcium influxes, by performing the assays in EGTA, abrogated FcγR-mediated IL-12(p40) mRNA suppression. Second, exposure of macrophages to the calcium ionophores, ionomycin or A23187, mimicked receptor ligation and inhibited IL-12(p40) mRNA induction by LPS. Finally, bone marrow–derived macrophages from FcR γ chain–deficient mice, which fail to flux calcium after receptor ligation, failed to inhibit IL-12(p40) mRNA induction. These results indicate that the calcium influxes that occur as a result of receptor ligation are responsible for inhibiting the induction of IL-12 by LPS. Hence, the ligation of phagocytic receptors on macrophages can lead to a dramatic decrease in IL-12 induction. This downregulation may be a way of limiting proinflammatory responses of macrophages to extracellular pathogens, or suppressing the development of cell-mediated immunity to intracellular pathogens.

Increased expression of Fcγ receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor α and matrix metalloproteinase

“…However, one would then expect that other cytokines, such as TNF␣, would also be down-regulated. A more plausible explanation may be that IC stimulation causes inhibition of IL-12 production by macrophages, as was previously reported by Sutterwala et al and Grazia Cappiello et al (58,59). Unfortunately, IL-12 production could not be detected in the culture supernatants, either in the presence or absence of HAGG stimulation (data not shown), leaving us unable to show this inhibition of IL-12 production in our in vitro system.…”

The Classical and Regulatory Functions of C1q in Immunity and Autoimmunity

“…Besides phagocytosis, the opsonic iC3b potentially promotes immune suppression or tolerance in phagocytes through stimulating CR3-simultaneous CR3 ligation inhibits LPS induction of IL-12 from macrophages (35,36). IL-12 is produced by antigen-presenting cells (APCs), like macrophages and DCs, and plays a major role in host T differentiation into IFN-γ producing Th1 cells (37).…”

“…Ligation of the iC3b receptor CR3 on macrophages inhibits IL-12 production (35,36). Phagocytosis of iC3b-opsonized AC by DCs renders these cells tolerogenic (25).…”

Transcriptional Inhibition of Interleukin-12 Promoter Activity in Leishmania Spp.–Infected Macrophages

“…killing is indeed delayed (Melby, 1991). Inhibition of MP IL-12 production and resulting Th1 responses is not unique to Leishmania; viruses (Chehimi et al, 1994;Chougnet et al, 1996;Karp et 1996) and bacteria (Marth and Kelsall, 1997;Sutterwala et al, 1997;Matsunaga et al, 2003) also exploit this mechanism to avoid clearance.…”

“…killing is indeed delayed (Melby, 1991). Inhibition of MP IL-12 production and resulting Th1 responses is not unique to Leishmania; viruses (Chehimi et al, 1994;Chougnet et al, 1996;Karp et 1996) and bacteria (Marth and Kelsall, 1997;Sutterwala et al, 1997;Matsunaga et al, 2003) also exploit this mechanism to avoid clearance.The general nature of impaired IL-12 production in Leishmania spp.-infected MP has extended to every IL-12 agonist that has been tested. Leishmania spp.-infected MP are unable to produce IL-12 even in response to strong inflammatory stimuli, including microbial stimuli, e.g., lipopolysaccharide (LPS), Staphylococcus aureus (SAC), Toxoplasma gondii antigen, and mycobacteria (Carrera et al, 1996;Sartori et al, 1997;Belkaid et al, 1998;Weinheber et al, 1998;Piedrafita et al, 1999), and T-cell-dependent agonists, e.g., IFN-γ and CD40L (Carrera et al, 1996;Belkaid et al, 1998;Weinheber et al, 1998;Piedrafita et al, 1999).…”